Peter J. Mackrell

Pancreatic anastomotic failure after pancreaticoduodenectomy

BACKGROUND Pancreatic anastomotic failure has historically been regarded as one of the most feared complications after pancreaticoduodenectomy. METHODS We reviewed our recent experience (59 cases), March 1994 to December 1998, with pancreaticoduodenectomy and compared preoperative and intraoperative characteristics as well as outcomes in those patients who experienced (n = 10) versus those who did not experience a postoperative pancreatic leak (n = 49). Information was retrospectively collected from hospital records, office records, and interviews with patients. RESULTS The clinical leak rate in this series was 8.5%. There were no significant differences in preoperative or intraoperative characteristics comparing those with versus those without a postoperative pancreatic leak. Only 1 of 10 patients with a postoperative pancreatic leak required reoperation to manage the leak. Those with a pancreatic leak had more other postoperative complications (median 2 versus 0 complications per patient, P = 0.01) and longer hospital duration compared with those without a leak (median 13 versus 23 days, P<0.01). Overall mortality in the series was 3.4%; no mortalities occurred as a result of a pancreatic leak. CONCLUSIONS In the 1990s pancreatic anastomotic leak remains a potentially lethal problem after pancreaticoduodenectomy. Pancreatic leakage after pancreaticoduodenectomy is associated with other postoperative complications and a longer hospital stay.

Blocking prostaglandin E2 after trauma attenuates pro-inflammatory cytokines and improves survival.

Major injury leads to impaired immune responses and increases the risk of infectious complications. Following trauma, increased prostaglandin E2 (PGE2) levels may be important in immunodysregulation. We hypothesized that blocking PGE2 with NS-398, a selective COX-2 inhibitor, during the first 24 h after injury may modify the immune response and protect the host from a subsequent septic challenge. BALB/c mice were given NS-398 (10 mg/kg) immediately after injury, at 12, and at 24 h after sham injury or trauma (femur fracture and 40% hemorrhage). On day 7 after injury, splenic macrophages were evaluated for cytokine production and COX-2 mRNA. In a separate study mice were injured, then given 3 doses of NS-398. After 7 days, cecal ligation and puncture was performed and mice were followed for survival. Traumatized mice given NS-398 had a significant survival advantage compared with trauma mice alone (P < 0.001). Macrophages from traumatized mice showed increased COX-2 mRNA and proinflammatory cytokines compared with controls (P < 0.05), whereas treatment of injured mice with NS-398 significantly decreased proinflammatory cytokine production (P < 0.05) and COX-2 mRNA. Therefore NS-398 given within 24 h of injury suppressed PGE2 through inhibition of cyclooxygenase, in addition to decreasing proinflammatory cytokines, and providing a survival advantage to the host.

Overlapping CRE and E-box promoter elements can independently regulate COX-2 gene transcription in macrophages.

Macrophage cyclooxygenase‐2 (COX‐2) transcription is mediated through the collaboration of different promoter elements. Here, the role of an overlapping cyclic AMP responsive element (CRE)/E‐box was investigated. Nuclear proteins bound both the CRE and E‐box, which synergized with other promoter elements to induce COX‐2 transcription. Endotoxin induced binding of nuclear proteins to the CRE and E‐box and each element independently induced higher COX‐2 transcription levels than the overlapping CRE/E‐box. Transcription factors associated with the CRE binding complex included c‐Jun and CRE binding protein and with the E‐box binding complex USF‐1; their overexpression significantly induced COX‐2 transcription. Therefore, both CRE and E‐box promoter elements regulate COX‐2 transcription in macrophages.

Glucocorticoid blockade does not abrogate tumor-induced cachexia.

Cancer-induced cachexia is a common manifestation observed in patients with malignancies. Elevated levels of circulating glucocorticoids and interleukin-6 (IL-6) have been observed in cancer patients with cachexia and are implicated as major mediators in this process. The purpose of this study was to investigate the role of circulating glucocorticoid levels as primary mediators in cancer-induced cachexia. We evaluated whether inhibition of glucocorticoids with the receptor antagonist RU-486 could abrogate the detrimental wasting of muscle and adipose tissues seen in a well-characterized murine tumor-induced cachexia model. Mice (12/group) were randomized to control, tumor-bearing, control + vehicle, or tumor-bearing + glucocorticoid receptor antagonist groups. Circulating serum glucocorticoid and IL-6 levels were measured in addition to multiple body composition parameters, such as total body weight, lean body mass, and adipose content. The results of this study indicate a significant physiological alteration in the tumor-bearing host that causes severe and detrimental changes in body composition parameters. Regression analysis demonstrated a significant correlation between increased circulating glucocorticoid levels and alterations in body composition parameters. These observed defects were not abrogated with the administration of a glucocorticoid receptor antagonist. We therefore conclude that the untoward effects of tumor-induced cachexia are not mediated primarily by the peripheral effects of high circulating glucocorticoid levels but may involve a complex interaction with IL-6.

Serum leptin levels in acute protein deprivation.

BACKGROUND Protein energy malnutrition (PEM) induces a host neuroendocrine response, reflected by significant elevations in circulating glucocorticoid levels and associated with metabolic and immune dysfunction. Leptin regulates food intake and body mass and has a significant impact on the hypothalamic-pituitary-adrenal axis (HPA). We hypothesized that leptin may be altered by and may play an important role in regulating the effects of PEM. METHODS Female Balb/c mice were used. In experiment 1, mice were pair-fed either a protein-free (0% casein) or control (24% casein) diet for 7 days. In experiment 2, mice were implanted with either a placebo or corticosterone-releasing pellet and fed the control diet for 7 days. In experiment 3, adrenalectomized mice were pair-fed either the protein-free or control diet for 7 days. Serum corticosterone and leptin levels were measured in all experiments. RESULTS PEM caused significant reductions in food intake, body weight, and total body fat, but not lean body mass. Serum corticosterone and leptin levels were significantly greater in mice fed the protein-free diet. Subcutaneous implantation of a corticosterone pellet in mice fed the control diet resulted in a significantly elevated serum leptin level compared with placebo-implanted controls. Bilateral adrenalectomy partially blunted the increased serum leptin in PEM. CONCLUSIONS Leptin may be an important mediator of weight loss and decreased food intake in PEM. Elevated serum leptin in PEM may be secondary to elevated serum corticosterone, with other factors inherent in the host response to protein restriction also contributing to elevated serum leptin.